As medical advances improve morbidity and mortality in sickle cell disease (SCD), improving reproductive health is of increasing importance. Knowledge gaps include limited safety information for hormonal contraception and the impact of pre-pregnancy hydroxyurea (HU) use on pregnancy outcomes. Estrogen-containing contraceptives increase the risk of thromboembolism (TE), and there is little evidence on the safety of progestin-only contraceptives for women with SCD. Lack of safety data can be a barrier to provision of contraception for medically complex women. This is a particular concern for women with SCD, given the increased risk of mortality and morbidity during pregnancy, and the high rates of unplanned pregnancy. During pregnancy, women with SCD have increased risk of mortality, preeclampsia, and preterm delivery compared to race-matched peers. However, most of these data are 10-25 years old, when use of HU, a highly efficacious disease modifying therapy, was substantially lower. While the impact of HU on outcomes such as vaso-occlusive crises and acute chest syndrome is well described, the impact of pre-pregnancy HU use on pregnancy outcomes is unexplored. The objective of this R21 application is to combine our methodologic experience in large database research and our content expertise in women?s hematology and SCD to utilize health claims data to study contraception safety and pregnancy outcomes in women with SCD. The specific aims of this application are: 1) compare safety of contraceptive choices among women with SCD by identifying the hazard rate of TE in women prescribed progestin-only, estrogen-containing, or no hormonal contraception, and 2) compare pregnancy outcomes in women with SCD with and without HU exposure pre-pregnancy, and outcomes in women with SCD compared to age and race-matched controls. We hypothesize that time to TE in women using progestin-only contraception will be non-inferior to time to TE in women not using contraception, independent of age or SCD severity. We also hypothesize that pregnancy complications will be higher in women without HU use pre-pregnancy, again controlling for age and SCD severity. Finally, we hypothesize that current relative risks of preeclampsia and pre- term delivery in women with SCD compared to controls will be significantly lower compared to historical data. The proposed work is innovative because it addresses questions that have either not been studied (impact of pre-pregnancy HU exposure on clinical outcomes) or studied only in very small cohorts (contraception safety). Completion of this award will yield the following expected outcomes: 1) knowledge of the absolute risk of contraception-related TE in SCD and identification of the safest forms of contraception, and 2) demonstration of the impact of pre-pregnancy HU use on pregnancy outcomes. The proposed work is significant because understanding contraception safety is the first step to eliminating barriers to counseling and prescribing to a patient population with increased risks of adverse pregnancy outcomes. As well, better understanding of the impact of pre-pregnancy HU use on pregnancy may be key in promoting use of and adherence to HU.